1. Field of the Invention
The invention generally relates to the field of medicinal chemistry. More specifically, the invention relates to the administration of beta-carotene and/or vitamin E to inhibit the occurrence of a major vascular event. The invention is further directed to pharmaceutical compositions comprising beta-carotene in combination with vitamin E. In one embodiment, beta-carotene is administered in combination with aspirin.
2. Brief Description of the Background Art
Despite a recent decline in cardiovascular disease-related mortality, cardiovascular disease remains the leading cause of morbidity and mortality in men and women in the United States, accounting for 47% of all deaths in 1986 (Dept. of Health and Human Services, Mortality Part B 88-1114:170-95 (1988).
Recent evidence suggests that antioxidant therapy may prevent or impede atherogenesis. Free radical oxidation has been postulated to play a role in the pathogenesis of atherosclerotic disease (Steinberg et al., N. Engl. J. Med. 320(14):915-24 (1989)). Serum lipoproteins can become oxidized in vivo (Warso et al., J. Clin. Invest. 75:667-71 (1985)) and these may be more atherogenic than their unoxidized counterparts. Oxidized low density lipoprotein (LDL) can potentially promote atherogenesis by several mechanisms. First, these modified lipoproteins may be toxic to or alter function of arterial endothelium. Oxidized LDL is cytotoxic to cultured endothelial cells as well as fibroblasts in vitro (Hessler et al., Arteriosclerosis 3(3):215-22 (1983); Yagi, K., Bioessays 1:58-60 (1984)). This altered endothelium may permit diffusion of serum lipids into the subendothelium and/or alter the ability of the endothelium to prevent thrombosis. Second, oxidized LDL chemotactically attracts and immobilizes monocyte/macrophages (Quinn et al., Proc. Natl. Acad. Sci. 82:5949-53 (1985)), some of which are destined to become lipid-laden foam cells within atheromatous plaque (Schaffner et al., Am. J. Pathol. 100:57-73 (1980); Gerrity, R. G., Am. J. Pathol. 103:181-90 (1981)). Finally, oxidized LDL is taken up into foam cells via a scavenger receptor more readily than unoxidized LDL (Fogelman et al., Proc. Natl. Acad. Sci. 77:2214-18 (1980); Goldstein et al., Proc. Natl. Acad. Sci. 76:333-37 (1979)). Thus oxidation of LDL may play an important role in the initiation and propagation of atherosclerosis.
Recent attention has focused on agents that may prevent the oxidation of LDL and thus impede or retard the progression of atherosclerosis. When incubated in various cell preparations, LDL will become oxidized (Morel et al., Artheriosclerosis 4:357-64 (1984); Cathcort et al., J. Leukocyte Biol. 38:341-50 (1985)). This process can be inhibited by the addition to the cell preparation of antioxidants such as butylated hydroxytoluene or vitamin E (Morel et al., Artheriosclerosis 4:357-64 (1984); Steinbrecher, et al., Arteriosclertosis 1:135-43 (1987)). LDL taken from patients treated with probucol, a cholesterol-lowering agent with lipid antioxidant properties, does not become oxidized in an endothelial preparation that does oxidize LDL from untreated patients (Parthasarathy et al., J. Clin. Invest. 77:641-44 (1986)). This in vitro data suggests that antioxidant therapy may reduce the rate of in vivo lipid oxidation. In addition, after controlling for its lipid-lowering effect, probucol reduced the rate of fatty-streak formation in Watanabe heritable hyperlipidemic rabbits (Carew et al., Proc. Natl. Acad. Sci. 84:7725-29 (1987)).